Primary biliary cirrhosis (PBC) is a disease of unknown etiology characterized by slowly progressive intrahepatic cholestasis due to non-suppurative, presumably autoimmune, destruction of septal and the larger interlobular bile ducts. Because certain other autoimmune diseases appear to respond favorably to alkylating agents, a controlled trial of chlorambucil therapy for patients with symptomatic PBC has been conducted. Twenty-four patients were admitted to this trial: 13 were randomized to receive chlorambucil therapy (0.5-4.0 mg/day) and 11 to the control (no treatment) group. The dose of chlroambucil was adjusted to reduce the peripheral blood lymphocyte count by 50% and maintain the poly-morphonuclear leukocyte count above 1000 per c.mm. All patients have been followed for 2-6 years (mean = 4.1 years). During follow-up, two patients died: both were controls. Mean serum bilirubin levels decreased slightly in the treated group but increased significantly in the controls. At 2 years the mean serum albumin was significantly improved in treated patients but was decreased in controls. Mean serum transaminase levels were significantly less in treated patients than in controls. Means serum immunoglobulin (IgM and IgG) levels decreased from elevated values to values within the normal range in all chlorambucil-treated patients, but did not change appreciably in controls. Liver biopsy histopathology after one and/or two years revealed significantly less inflammation, slightly less fibrosis and less progression of the stage of disease in the treated than in the control patients. Potential side effects of chlorambucil therapy included the onset of menopause in two patients, localized herpes simplex or zoster in 3 and, in 4 patients, persistent leukopenia or thrombocytopenia requiring discontinuation of the drug. These findings strongly suggest that chlorambucil therapy retards the progression of PBC, and they provide an impetus to search for safer (e.g. noncarcinogenic) and more effective immunosuppressive regimes for the treatment of this disease.